Even modest amounts of weight reduction have beneficial impact on the co-morbidities of obesity. However, long term maintenance of reduced body weight is rare. Our central hypothesis is that the molecular physiology of the regulation of body fat stores is designed to maintain these stores above a minimal level that is determined by genetic and other factors. Reduction of energy stores below this threshold invokes compensatory responses in food intake and energy expenditure that function to restore body fat. A primary signal that triggers these CNS-mediated changes is the adipocyte- derived hormone, leptin. We have shown that in both never-obese and obese humans, maintenance of a 10% or greater reduction in body weight results in reduced energy expenditure due primarily to increased skeletal muscle work efficiency and increased hunger that act coordinately to promote restoration of body energy stores. We have also shown that many of these changes are normalized by administration of exogenous leptin in doses sufficient to restore circulating concentrations of leptin to those present prior to weight loss. The proposed studies focus on: Specific Aim #1, the in vivo neuro/behavioral biology of the weight-reduced state;and Specific Aim #2, the molecular physiology of the increased skeletal muscle work efficiency in the same weight-reduced subjects. At usual body weight, following a 10% weight reduction, and at reduced weight plus hormone replacement ( with leptin or T3), obese and non-obese subjects (living in a clinical research center) will undergo quantitative studies of body composition, compartmentalized energy expenditure ingestive behavior, autonomic nervous system activity, regional neuronal activity related to energy intake by fMRI, chemical analysis of CSF for neuropeptides/neurotransmitters and metabolites, functional neuroendocrine status of thyroid and adrenal axes, chemo-mechanical function in skeletal muscle by in vivo and in vitro methods. PUBLIC HEALTH RELEVANCE: Obesity now constitutes perhaps the single greatest (and growing) health problem in the U.S. as reflected in numbers of affected adults and children, and contribution to major, costly illnesses such as diabetes and cardiovascular disease. A major aspect of the biology of weight regulation is the tenacity with which the body defends its fat content, compensating for fat loss by lowering energy expenditure and increasing hunger, leading thereby to regain of lost weight. The goal of the proposed studies is to understand the relevant biology sufficiently well to be able to modify or prevent such compensation, thereby enabling successful maintenance of therapeutic weight loss.